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  1. Switch Safety and Efficacy of Crossover (Switch) from UFH/Enox to Bivalirudin: Results from ACUITY Dr. Harvey White Green Lane Cardiovascular Service Auckland City Hospital, Auckland, NZ Switch

  2. Disclosure • Research Grants : • Alexion Fournier Laboratories Sanofi Aventis Johnson & Johnson Eli Lilly Proctor & Gamble • Merck Sharpe & DohmeSchering PloughRoche • The Medicines CompanyGlaxo Smith Kline Pfizer • Neuren Pharmaceuticals NIH • Consultant: • Sanofi Aventis The Medicines Company

  3. Background • ACS patients • 87% of patients receive either UFH or Enox within 24 hours after admission1 • 72% of patients in Synergy and 50 % of patients in OASIS- 5received prior antithrombin2,3 • Published studies and perceptions • Patients in Synergy who crossed over between UFH and Enox had an increase in bleeding complications2 • This activity occurred at various times through the study period: at times in response to clinical or clinician perception • Consistent therapy is better4 1 CRUSADE( 1Q-2006 results); 2 Synergy results; JAMA 2004; 3 OASIS -5; Yusuf et al,NEJM 2006; 4 Cohen et al, JACC 2006;

  4. Scope of Analysis • This analysis will address the question of the safety and efficacy of switching from indirect thrombin inhibition (UFH or Enox) to direct thrombin inhibition (bivalirudin) • A protocol-driven activity of the ACUITY study at the time of randomization

  5. PNI <0.001 PSup = 0.015 PNI = 0.011 PSup = 0.32 PNI <0.001 PSup <0.001 ACUITY: Primary results • Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone *Heparin=unfractionated or enoxaparin

  6. Study Medications • Anti-thrombin agents (started pre angiography) 1 Target aPTT 50-75 seconds 2 If last enoxaparin dose ≥8h - <16h before PCI; 3 If maintenance dose discontinued or ≥16h from last dose 4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if GPIIb/IIIa inhibitor not used 5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before 6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion

  7. Prior treatment • ACUITY Protocol requirements • Patients on an antithrombin (either UFH or Enox) prior to randomization: • Continued the same treatment if randomized into Heparin(s) + GP IIb/IIIa arm • Switched to bivalirudin if randomized to one of the bivalirudin arms • Following results of Synergy UFH was allowed in the trial • Sites prospectively determined the preferred anti-thrombin strategy of either UFH or Enox • Switch between UFH and Enox was not permitted

  8. Current Analysis • Hypothesis • Bivalirudin improves bleeding outcomes while preserving ischemic protection for ACS patients even if the patients are switched from either UFH or enoxaparin to bivalirudin (monotherapy) at the time of presentation. • Is it better to switch to bivalirudin or remain on consistent therapy?

  9. Current Analysis • Methods • Patients on prior antithrombin • Consistent: No switching from pre-randomization anti-thrombin to randomized therapy: • Enox →Enox or UFH → UFH • Switch: Single switch to bivalirudin determined by randomization code • from Enox → bivalirudin or UFH →bivalirudin • Event rates at 30-days • Net Clinical Outcome • Ischemic Composite • Major Bleeding

  10. ACUITY Primary Endpoints at 30 days • Net Clinical Endpoint • Composite ischemic and non-CABG major bleeding endpoints • Ischemic Endpoint • Death, MI, or unplanned revascularization • Non-CABG Major Bleeding Endpoint • Intracranial, intraocular, or retroperitoneal bleeding • Access site bleed requiring intervention/surgery • Hematoma ≥5 cm • Hgb ≥3g/dL with an overt source or ≥4g/dL w/o overt source • Blood transfusion

  11. Consort Diagram ACUITYN = 13819 Arm AHeparins + IIb/IIIaN = 4603 Arm B Bivalirudin + GP IIb/IIIaN = 4604 Arm CBivalirudinN = 4612

  12. Consort Diagram ACUITYN = 13819 Arm AHeparins + IIb/IIIaN = 4603 Arm CBivalirudinN = 4612

  13. Consort Diagram ACUITY13819 Pts on Prior ATN = 6606 ╪ Arm A: CONSISTENTHeparins + IIb/IIIaN = 2223 Arm C: SWITCHBivalirudinN = 2237 • ╪ excludes Arm B and pts. with multiple crossovers, missing data

  14. Consort Diagram UFH→UFHN = 1294 UFH→BivN = 1313 Enox→EnoxN = 929 Enox→BivN = 857 ACUITY13819 Pts on Prior ATN = 6606 ╪ CONSISTENTUFH/EnoxN = 2223 SWITCHBivalirudin*N = 2237 • * Includes 67 pts. who had UFH and Enox • ╪ excludes Arm B and pts. with multiple crossovers, missing data

  15. Baseline Characteristics Consistent UFH/Enox vs. Switch to Biv * creatinine clearance <60 mL/min *Elevated cardiac markers and/or ST changes

  16. 0.77 [0.63 – 0.91] 0.95 [0.76 – 1.17] 0.47 [0.35 – 0.64] P=0.002 P=0.601 P<0.001 Consistent vs. Switch Comparing Consistent therapy on UFH/Enox vs. Switch Bivalirudin Alone

  17. Consistent vs. SwitchAll Patients - Adjusted OR (95% CI) P-value Odds ratio±95% CI Ischemia 1.10 (0.86-1.41) 0.464 Major Bleeding <0.001 0.47 (0.34-0.65) Net Clinical Outcome 0.83 (0.67-1.02) 0.073 Switch to Bivalirudin alone better Consistent UFH/Enox better * Comparing consistent Hep/Enox vs Switch Bivalirudin

  18. Consistent vs. SwitchHigh Risk - Unadjusted Comparing Consistent UFH/Enox vs Switch Bivalirudin

  19. Consistent vs. SwitchHigh Risk - Adjusted Comparing Consistent UFH/Enox vs Switch Bivalirudin OR (95% CI) P-value Odds ratio±95% CI Ischemia 1.11 (0.85-1.46) 0.445 Major Bleeding <0.001 0.51 (0.36-0.72) Net Clinical Outcome 0.86 (0.68-1.07) 0.177 Switch to Bivalirudin alone better Consistent UFH/Enox better

  20. Consistent vs. SwitchPatients undergoing PCI - Unadjusted Comparing Consistent UFH/Enox vs Switch Bivalirudin

  21. 0.81 [0.61 – 1.07] 0.92 [0.65 – 1.30] 0.54 [0.34 – 0.88] P=0.145 P=0.626 P=0.013 Consistent vs. Switch Comparing Consistent therapy on Enox vs. Switch from Enox to Bivalirudin Alone

  22. 0.75[0.60 – 0.94] 0.98[0.74 – 1.28] 0.44[0.30 – 0.65] P=0.012 P=0.857 P<0.001 Consistent vs. Switch Comparing Consistent therapy on UFH vs. Switch from UFH to Bivalirudin Alone

  23. Consistent vs. SwitchAdjusted Comparing Consistent UFH/Enox vs Switch to Bivalirudin Consistent Enox vs. bivalirudin Consistent UFH vs. bivalirudin OR (95% CI) OR (95% CI) Odds ratio±95% CI P-value Odds ratio±95% CI P-value 1.07 (0.72-1.59) 1.18 (0.86-1.63) 0.732 0.312 Ischemia Ischemia MajorBleeding MajorBleeding 0.032 <0.001 0.55 (0.32-0.95) 0.40 (0.26-0.61) Net ClinicalOutcome Net ClinicalOutcome 0.472 0.89 (0.64-1.23) 0.78 (0.59-1.03) 0.081 Switch to Bivalirudinalone better Consistent Enoxbetter Switch to Bivalirudinalone better Consistent UFHbetter

  24. Limitations • Post-hoc subgroup analysis • Pre-randomization use of anti-thrombin was not stratified • Timing and dose of last UFH and Enox was not collected in the CRF

  25. Conclusions • Switching to bivalirudin is safe • Switching from any heparin (either enoxaparin or UFH) to bivalirudin monotherapy is not associated with an increased risk for ischemic events. • Furthermore • Switch to bivalirudin provides patients the 50% bleeding advantage of bivalirudin compared with consistent therapy on UFH or enoxaparin.